CN119528857A

CN119528857A - A kind of synthetic method of 5-methoxy-3-benzofuranone

Info

Publication number: CN119528857A
Application number: CN202411429506.4A
Authority: CN
Inventors: 张锐豪; 郦荣浩; 陈华; 倪强; 郭小燕
Original assignee: Shanghai Bichen Biochemical Technology Co ltd
Current assignee: Shanghai Bichen Biochemical Technology Co ltd
Priority date: 2024-10-14
Filing date: 2024-10-14
Publication date: 2025-02-28

Abstract

The invention provides a synthesis method of 5-methoxy-3-benzofuranone, which takes 2-hydroxy-5-methoxy acetophenone as a raw material, firstly converts the 2-hydroxy-5-methoxy acetophenone into an intermediate 2 (2-bromo-1- (2-hydroxy-5-methoxy phenyl) ethanone), and converts the intermediate 2 into a target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. In the key steps of the synthesis method, alkali is not used, but silica gel powder is used for replacing alkali, so that the post-reaction treatment and purification are simple, the reaction and time cost is greatly reduced, and the process amplification can be realized.

Description

Synthesis method of 5-methoxy-3-benzofuranone

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 5-methoxy-3-benzofuranone.

Background

The compound 5-methoxy-3-benzofuranone is an important molecular building block, 5-methoxy-3-benzofuranone is used as a key intermediate in the synthesis of 3, 4-dihydro-2H-pyrano [3,2-b ] benzofuran-2-one skeleton compounds in patent CN112174974A, the 3, 4-dihydro-2H-pyrano [3,2-b ] benzofuran-2-one skeleton compounds have the application in the aspects of resisting tumor, resisting leukemia, resisting bacteria, resisting inflammation, resisting cancer, reducing blood sugar, inhibiting platelet aggregation, promoting long-term memory and the like, 5-methoxy-3-benzofuranone is also used as a key intermediate in the synthesis of 2, 3-dihydro-benzofuran compounds, the compounds can be used for treating or preventing melatonin related diseases, and 5-methoxy-3-benzofuranone is also used as an intermediate in the synthesis of 3-piperidine-4-acyl-1H-indole and 3- (1, 6-tetrahydropyridine) -1H-indole and 3- (1, 6-4-acyl) -indole derivatives such as the derivatives can be used for treating or preventing depression and the like in patent US 2005/004162. Therefore, it is of great importance to study the synthesis of 5-methoxy-3-benzofuranone.

In the prior art, under the action of alkali, the compound 2-bromo-1- (2-hydroxy-5-methoxyphenyl) ethanone is converted into the compound 5-methoxy-3-benzofuranone, the reaction yield is low, post-treatment is required to be performed with column chromatography purification, the purification time cost is high, and the method is not suitable for process amplification.

Disclosure of Invention

Aiming at the defects of the synthesis method of 5-methoxy-3-benzofuranone in the prior art, the invention aims to provide the synthesis method of 5-methoxy-3-benzofuranone, which has the advantages of simple post-treatment, ideal yield and suitability for process amplification.

In order to achieve the above purpose, the invention adopts the following technical scheme:

the synthesis process of 5-methoxy-3-benzofuranone includes converting 2-hydroxy-5-methoxy acetophenone as material into intermediate 2 (2-bromo-1- (2-hydroxy-5-methoxy phenyl) ethanone), and converting the intermediate 2 into target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder, and has the following synthesis process:

further, the synthesis method of the 5-methoxy-3-benzofuranone comprises the following steps:

(1) Adding the compound 1, namely 2-hydroxy-5-methoxyacetophenone, into an organic solvent I, adding copper bromide, heating to reflux under the protection of inert gas, and stirring for reaction for 10-36 hours. After the reaction is finished, the reaction liquid is subjected to post-treatment to obtain a compound 2;

(2) Adding silica gel powder into water, adding a compound 2, adding an organic solvent II, reacting for 2-5 hours at room temperature, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain a target compound 5-methoxy-3-benzofuranone.

Further, in the step (1), the organic solvent I is one or more of ethyl acetate, tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, and methanol, and the 1, 4-dioxane.

Further, in step (1), the inert gas is selected from one or more of nitrogen or argon.

Further, in the step (1), the mass-volume ratio g/mL of the compound 1 to the organic solvent I is 1 (5-40).

Further, in the step (1), the molar ratio of the compound 1 to the copper bromide is 1 (1-5).

In the step (1), the post-treatment is to filter the reaction liquid, collect filtrate, spin-dry the filtrate to obtain crude product, and purify the crude product to obtain the compound 2.

Further, in step (1), the purification mode is selected from one or more of beating, column chromatography, recrystallization or distillation.

Further, in the step (2), the organic solvent II is acetonitrile or methanol or tetrahydrofuran or N, N-dimethylformamide or dimethyl sulfoxide.

Further, in the step (2), the mass ratio of the compound 2 to the silica gel powder is 1 (5-15).

In the step (2), methyl tertiary butyl ether is added into the reaction liquid for stirring, silica gel powder precipitation is waited for, then suction filtration is carried out, filtrate is collected, the filtrate is washed by water, saturated saline water is used for washing, the crude product is obtained after spin drying, and the crude product is purified to obtain the target compound 5-methoxy-3-benzofuranone.

Further, in the step (2), the purification mode is one or more of beating, column chromatography, recrystallization or distillation.

Compared with the prior art, the invention has the beneficial technical effects that:

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 5-methoxy-3-benzofuranone in example 1 of the present invention.

Detailed Description

In order to make the technical solution and advantages of the embodiments of the present invention more clear, the technical solution of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.

In the following examples, reagents and materials were used as commercially available unless otherwise specified.

The following examples synthesized 5-methoxy-3-benzofuranone starting from 2-hydroxy-5-methoxyacetophenone, which was first converted to intermediate 2 (2-bromo-1- (2-hydroxy-5-methoxyphenyl) ethanone), intermediate 2 was converted to the target compound 3 (5-methoxy-3-benzofuranone) by silica gel powder, which was synthesized as follows:

the technical scheme of the invention is further explained by the following examples.

Example 1

The compound 5-methoxy-3-benzofuranone was synthesized in this example as follows:

(1) Compound 1, namely 2-hydroxy-5-methoxyacetophenone (200.00 g,1.20mol,1.0 eq), was added to a mixed organic solvent of ethyl acetate (1.0L) and chloroform (1.0L), copper bromide (510.75 g,2.29mol,1.90 eq) was added, and the mixture was heated to reflux under nitrogen as an inert gas, followed by stirring for reaction for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (1.0L), the filtrate was collected, the filtrate was dried by spin to give a crude product, which was slurried with petroleum ether, filtered, and the solid was collected and dried to give compound 2 (quality 281.20g, purity 96%, yield 92%).

(2) Silica gel powder (2000.00 g) was added to water (2.0L), compound 2 (200.00 g,816.09mmol,1.0 eq) was added, and acetonitrile (1.0L) was added and reacted at 25℃for 2 hours. After the completion of the reaction, methyl tert-butyl ether (5.0L) was added to the reaction mixture and stirred, the silica gel powder was allowed to precipitate, then suction filtration was performed, the filtrate was collected, washed with water, saturated brine, and dried by spin to give a crude product, which was slurried with petroleum ether, filtered, and dried to give the objective compound 5-methoxy-3-benzofuranone (quality 131.10g, purity 98%, yield 96%).

The nuclear magnetic hydrogen spectrum of the obtained compound 3 (5-methoxy-3-benzofuranone) is shown in figure 1, and the characterization data are as follows:

¹H NMR(400MHz,cdcl₃)δ7.29–7.17(m,1H),7.16–6.87(m,2H),4.64(s,2H),3.80(s,3H).

Examples 2 to 7

Examples 2 to 7 are the same as example 1 except that the amount of silica gel powder used in step (2), the organic solvent II, the reaction temperature, the reaction time, etc. are adjusted as shown in Table 1.

The effect of each reaction condition on the reaction yield in the synthesis of the objective compound 3 (5-methoxy-3-benzofuranone) was confirmed by examples 1 to 7, and the results are shown in Table 1.

TABLE 1 Synthesis conditions and results for examples

As can be seen from table 1:

In comparative examples 1 to 3, the reaction effect was already excellent when the mass ratio of the compound 2 to the silica gel powder was 1:10.

Comparative examples 1, 4-5, the reaction was carried out in the solvents acetonitrile, dichloromethane and acetone, with acetonitrile being the solvent more effective.

In comparative examples 1 and 6, the reaction effect was optimized at a reaction temperature of 25 ℃.

In comparative examples 1 and 7, the reaction time was 2 hours, and the reaction effect was optimized.

The foregoing is a preferred embodiment of the present invention, but the present invention should not be limited to the disclosure of this embodiment. So that equivalents and modifications will fall within the scope of the invention, all within the spirit and scope of the invention as disclosed.

Claims

1. A method for synthesizing 5-methoxy-3-benzofuranone, characterized in that 2-hydroxy-5-methoxyacetophenone is used as a raw material, which is first converted into an intermediate 2 (2-bromo-1-(2-hydroxy-5-methoxyphenyl)ethanone), and the intermediate 2 is converted into a target compound 3 (5-methoxy-3-benzofuranone) under the action of silica gel powder. The synthetic route is as follows:

2. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 1, characterized in that it comprises the following steps:

(1) Compound 1, i.e., 2-hydroxy-5-methoxyacetophenone, is added to an organic solvent I, and then copper bromide is added. Under the protection of an inert gas, the mixture is heated to reflux and stirred for reaction for 10-36 hours. After the reaction is completed, the reaction solution is post-treated to obtain Compound 2;

(2) Add silica gel powder to water, add compound 2, and then add organic solvent II, and react at room temperature for 2-5 hours. After the reaction is completed, the reaction solution is post-treated to obtain the target compound 3, namely 5-methoxy-3-benzofuranone.

3. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that, in step (1), the organic solvent I is one or more of ethyl acetate, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ether, methyl tert-butyl ether, methanol, or 1,4-dioxane.

4. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that in step (1), the inert gas is one or more of nitrogen or argon.

5. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, wherein in step (1):

The mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) g/mL;

The molar ratio of the compound 1 to copper bromide is 1:(1-5).

6. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that in step (1), the post-treatment is filtering the reaction solution, collecting the filtrate, and spin-drying the filtrate to obtain a crude product, which is purified to obtain compound 2.

7. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 6, characterized in that in step (1), the purification method is one or more of pulping, column chromatography, recrystallization or distillation.

8. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that in step (2), the organic solvent II is acetonitrile or methanol or tetrahydrofuran or N,N-dimethylformamide or dimethyl sulfoxide.

9. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that, in step (2), the mass ratio of the compound 2 to the silica gel powder is 1:(5-15).

10. The method for synthesizing 5-methoxy-3-benzofuranone according to claim 2, characterized in that in step (2), the post-treatment is to add methyl tert-butyl ether to the reaction solution and stir, wait for the silica gel powder to precipitate, then filter, collect the filtrate, wash the filtrate with water, wash with saturated brine, and spin-dry to obtain a crude product, which is purified to obtain the target compound 5-methoxy-3-benzofuranone.